1. Field of the Invention
The present invention pertains to novel, potent anticonvulsants, antiepileptics, analgesics and cognition enhancers achieving their action through the antagonism of specific excitatory amino acid (EAA) neurotransmitter receptors. In particular, the invention is directed to .omega.-[2-(phosphonoalkylenyl)phenyl]-2-aminoalkanoic acids, their pharmaceutically acceptable salts and derivatives, and to the methods of synthesizing the same.
2. Description of the Prior Art
While L-glutamate and L-aspartate were initially thought merely to participate in brain metabolism, sufficient molecular pharmacological, biochemical and electrophysiological evidence now exists to suggest that these amino acids are neuroexcitatory transmitters [D. R. Curtis, A. W. Duggar, D. Felix, G. A. R. Johnston, A. K. Tebecis and J. C. Watkins. Brain Res. 41:283-301 (1972)].
For many years following the initial characterization of the neuro-excitotoxic actions of amino acis, it was tacitly assumed that all compounds of this type (agonists and antagonists) acted upon the same receptor. The discovery of relatively selective antagonists of different actions of EAA or of actions of different EAA compounds, has changed this perception, and it is now accepted that multiple recognition sites for EAA are present in the vertebrate central nervous system [J. C. Watkins and R. H. Evans. Ann. Rev. Pharmacol. Toxicol. 21:165-204 (1981)]. Defined by prototypical agonists or antagonists, these include:
1. receptors activated by L-Glutamate (Glu) and the conformationally restricted Glu analog, quisqualic acid (Quis), and antagonized selectively by glutamic acid diethylester,
2. receptors responsive to the synthetic analogue of L-aspartate (Asp), N-methyl-D-aspartate (NMDA), the isoxazole neurotoxin, ibotenic acid (Ibo), the pyridinedicarboxylic acid neurotoxin, quinolinic acid (Quin) and, probably, to Asp itself. These receptors are antagonized by D(-)-2-amino-5-phosphonopentanoic acid (AP5), D(-)-2-amino-7-phosphonoheptanoic acid (AP7), and the divalent cation, Mg++,
3. receptors activated by the pyrrolidine neuroexcitotoxin, kainic acid (KA), for which no specific antagonists have yet been identified and,
4. receptors antagonized by L(+)-2-amino-4-phosphonobutyric acid (LAP4). Originally identified as an EAA antagonist by electrophysiological means, LAP4 inhibits the response at the lateral perforant pathway synapses of the hippocampus to an unidentified endogenous excitatory substance. The possibility that Glu is this neurotransmitter is minimal and recent evidence suggests that the N-blocked dipeptide, N-acetylaspartyl-L-glutamate may function in this capacity [J. M. H. ff-French-mullen, K. J. Koller, R. Zaczek, Li Hori, J. T. Coyle and D. O. Carpenter. Proc. Nat. Acad. Sci. USA 82, 3897-4001 (1985)].
EAA's, possibly acting through one or more of these receptors, have been implicated in the etiology of various pathological conditions affecting the CNS. Thus, KA [K. Biziere, J. T. Slevin, R. Zaczek, J. C. Collins and J. T. Coyle. In: Advances in Pharmacology and Therapeutics (H. Yoshida, Y. Hagihara and S. Ebashi, eds) Pergamon, New York. pp. 271-276 (1982)], NMDA [R. Zaczek, J. Collins and J. T. Coyle. Neurosci. Letts 24:181-186 (1981)] and the endogenous excitatory amino acid Quin [R. Schwarcz, W. O. Whetsell and R. M. Mango. Science 219:316-318 (1983)] have been used to produce in animal models a syndrome analogous to human epilepsy and other convulsive disorders, and the anatomical and neurochemical lesions and deficiencies produced by such chemicals in animals with these compounds are similar to the characteristics seen postmortem in the brains of patient's dying of Huntington's disease [J. Coyle, and R. Schwarcz. Nature 263:244-246 (1976)] and epilepsy. Kainate administration can produce a limbic structure lesion that mimicks Ammon's Horn Sclerosis, an abnormality frequently found in temporal lobe epilepsy. Research on this model of temporal lobe epilepsy has suggested that endogenous EAA's may play a role in this disorder, that is particularly resistant to existing antiepileptics [J. V. Nadler, B. W. Perry, C. W. Cotman. Nature 271:676-677 (1978)]. In addition to Huntington's disease and epilepsy, it has been suggested that EAA's may contribute to Alzheimer's disease [A. C. Foster, J. F. Collins and R. Schwarcz. Neuropharmac. 22:1331-1341 (1983)], E. Roberts. In: Strategies for the development of an Effective Treatment for Senile Dementia (E. Crook and L. Gershon, eds.) Mark Power Assoc., New Camarin, Conn. pp. 247-230 (1981)], the neuronal death following stroke and other factors leading to cerebral ischemia, [R. P Simon, J. H. Swan, T. Griffiths and B. S. Meldrum, Science, 226, 850-852, (1984); S. Rothman. J. Neuroscience 4:1884-1891 (1984)] and hereditary olivopontocerebellar atrophy [J. T. Coyle, TINS 5:287-288 (1982)].
Because of the conceptual link between EAA activity at specific brain receptors in vitro and in vivo, excitotoxic lesions caused by EAA in animals, and the pathogeneis of the above neurodegenerative diseases, it is logical to explore pharmacologic means to antagonize endogenous excitatory and excitotoxic neurotransmitters. The development of antagonists of exogenous excitotoxins such as KA is also logical, since there is presumably and yet undiscovered specific endogenous substance that acts at brain KA receptors. The advent of potent and selective antagonists of EAA's exemplified by .alpha.-amino-.omega.-phosphonoalkylenylcarboxylic acids (the most potent and selective being D(-)-2-amino-7-phosphonoheptanoic acid, D(-)AP7 has provided a point of departure for the pharmacologic intervention of EAA action at their receptors.
Besides interfering with the neurotoxic and convulsive actions of NMDA, the exogenous excitotoxin, IBO, and the endogenous excitotoxin Quin (but not KA) [A. C. Foster and G. E. Fagg. Brain Res. Rev. 7:103-184 (1984); A. C. Foster, J. F. Collins and R. Schwarcz. Neuropharmac. 22:1331-1341 (1983); R. Schwarcz, J. F. Collins and D. A. Parks, Neurosci. Letts 33:85-90 (1982)], AP7 (i.c.v. and i.v.) protects against audiogenically-induced seizures in genetically susceptible mice [M. J. Croucher, J. F. Collins and B. S. Meldrum. Science 216:899-901 (1982)]. I.v. AP7 suppresses photically-induced myoclonus in the baboon [B. S. Meldrum. M. J. Croucher, G. Badman and J. F. Collins, Neurosi. Letts 39:101-104 (1983)], increases threshold current for electroshock induced seizures of mice and prevents chemically induced seizures in rodents [S. J. Czuczwar and G. Meldrum. Eur. J. Pharmac. 83:335-338 (1982)]. Very recently, AP7 (intrahippocampally) has been reported to markedly reduce or eliminate ischemic brain damage in the rodent carotid artery occlusion model of stroke [R. P. Simon, J. H. Swan, T. Griffiths and B. S. Meldrum. Science 226:850-852 (1984)], and another, less potent, EAA antagonist .delta.-D-glutamyl glycine, has been shown to protect cultured at hippocampal neurones from degeneration under conditions of oxygen depletion while blocking the toxicity of exogenously applied Glu and Asp [S. Rothman. J. Neuroscience 4:1884-1891 (1984)]. Recently, kainate and quisqualate receptor antagonists have also been shown to posses anticonvulsant activity [M. J. Croucher, B. S. Meldrum, A. W. Jones and J. C. Watkins. Brain Res. 377:111-114 (1984)]. Finally, and significantly, several lines of circumstantial evidence link excitatory amino acids, especially glutamate, with the onset of age-associated neurodegenerative diseases, including Alzheimer's disease [J. T. Greenamyre, J. B. Penney, A. B. Young, C. D'Amato, S. P. Hicks, I. Schoulson, Science 227:1496-1498 (1985)], and with tardive dyskinesia [J. W. Olney. In: Excitotoxins (K. Fuxe, R. Roberts, and R. Schwarcz, eds)].